tbuckley/cabot-search huggingface dataset:
Abstract 2612: Depleting EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer
Authors: Lu Yang, Arup Bhattacharya, Yun Li, Sandra Sexton, Xiang Ling, Fengzhi Li, Yuesheng Zhang
Journal: Cancer Research (2022)

Abstract Background &amp; Goals: Epidermal growth factor receptor (EGFR), an oncogenic receptor tyrosine kinase, is a major therapeutic target in several types of cancers. Several EGFR inhibitors are used to treat EGFR-positive colorectal cancer (CRC). Unfortunately, primary and acquired resistance to the inhibitors is very common. Current approaches to combating the resistance include combining EGFR inhibitors with agent(s) that targets compensatory signaling molecules (HER2, HER3, IGF1R, MET, KRAS, BRAF and PIK3CA). However, responses to such combination treatments are modest, if any. Overcoming drug resistance remains a major unmet medical need in EGFR-positive CRC. Results: Here, we show the main reason for CRC resistance to EGFR inhibitors and a therapeutic strategy that overcomes it. The sensitivity of CRC cells to EGFR inhibitors correlates with EGFR downregulation. PEPDG278D, a recombinant human protein that induces the degradation of both EGFR and HER2, strongly inhibits oncogenic signaling and growth of CRC in vitro and in vivo (subcutaneous tumors, orthotopic tumors, and patient-derived xenografts), regardless of activating mutations of KRAS, BRAF and PIK3CA. siRNA knockdown of EGFR or HER2 also inhibits CRC cells resistant to EGFR inhibitors. PEPDG278D indirectly suppresses HER3, IGF1R and MET by disrupting their heterodimerization with EGFR or HER2. While excessive tumor-generated EGFR ligands may block target engagement by PEPDG278D, inhibiting ligand shedding by aderbasib enables PEPDG278D to exert strong antitumor activity, and fluorouracil further enhances tumor inhibition. Collectively, our study shows that CRC resistance to EGFR inhibitors result primarily from their inability to eliminate their target and a PEPDG278D-centered combination treatment overcomes the resistance. Conclusions &amp; Therapeutic Relevance: The therapeutic activity of PEPDG278D highlights that EGFR and HER2 remain indispensable to the survival of CRC cells resistant to EGFR inhibitors. The strong therapeutic activity of PEPDG278D-centered combination treatment in preclinical models of CRC, which carry clinically relevant gene mutations that confer resistance to current EGFR inhibitors, provides the scientific premise for potential evaluation of this recombinant human protein in patients with drug-resistant CRC. Citation Format: Lu Yang, Arup Bhattacharya, Yun Li, Sandra Sexton, Xiang Ling, Fengzhi Li, Yuesheng Zhang. Depleting EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2612.
Abstract LB032: CXCR7 drives prostate cancer growth through AURKA activation
Authors: Galina Gritsina, Zhuoyuan Lin, Ka Wing Fong, Xiaodong Lu, Changsheng Zhao, Jindan Yu
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer among males in the United States. The mainstay treatment for metastatic PCa patients is androgen-deprivation therapies, including high-affinity androgen receptor antagonists, such as enzalutamide. Unfortunately, most patients develop resistance and relapse with castration-resistant PCa (CRPC). We have previously reported up-regulation of CXCR7, an atypical chemokine receptor, in CRPC. CXCR7 interacts with beta-arrestin (ARRB2), a cytoplasmic scaffold protein, and translocates to the cytoplasm to induce signal transduction and PCa progression. However, much remains to be known regarding CXCR7-driven downstream signaling and its therapeutic targeting in advanced PCa. To unveil CXCR7-downstream signaling, we utilized RNA-seq to profile gene expression. Gene ontology analyses revealed remarkable enrichment of CXCR7-regulated genes in G2/M cell cycle progression. Comprehensive phospho-proteomics analysis of CXCR7-knockdown PCa cells showed markedly reduced phosphorylation of AURKA substrates. AURKA, a serine/threonine-protein kinase, is a key regulator of mitosis and G2/M progression and is frequently upregulated in CRPC and the late-stage neuroendocrine PCa (NEPC). Activated AURKA experiences autophosphorylation and phosphorylates downstream substrates, e.g., TACC3, that mediate proper cell division. Immunoblotting confirmed that CXCR7 depletion reduces phosphorylation of AURKA and TACC3. Co-immunoprecipitation revealed protein-protein interaction between CXCR7 and AURKA, which is mediated by ARRB2. Accordingly, ARRB2-knockdown similarly inhibits AURKA phosphorylation and arrests cell proliferation. Immunofluorescence coupled with confocal imaging demonstrated that CXCR7 is packed into clathrin-coated vesicles and locates in the plasma membrane, cytoplasm, and perinuclear Golgi complex, which surrounds the centrosomal AURKA and ARRB2. We found that CXCR7 translocates to the Golgi complex along microtubule-dependent trafficking. Finally, we found that pharmacological inhibitors of AURKA abolish CXCR7-driven PCa cell proliferation in vitro and tumor growth in vivo. Conclusions: Our results describe for the first time that the CXCR7-ARRB2 complex interacts with AURKA and promotes its activation. Our data suggest that AURKA-targeting is a promising therapeutic strategy for CRPC and NEPC with CXCR7 up-regulation. Citation Format: Galina Gritsina, Zhuoyuan Lin, Ka Wing Fong, Xiaodong Lu, Changsheng Zhao, Jindan Yu. CXCR7 drives prostate cancer growth through AURKA activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB032.
MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre study
Authors: Behfar Ehdaie, Clare M Tempany, Ford Holland, Daniel D Sjoberg, Adam S Kibel, Quoc-Dien Trinh, Jeremy C Durack, Oguz Akin, Andrew J Vickers, Peter T Scardino, Dan Sperling, Jeffrey Y C Wong, Bertram Yuh, David A Woodrum, Lance A Mynderse, Steven S Raman, Allan J Pantuck, Marc H Schiffman, Timothy D McClure, Geoffrey A Sonn, Pejman Ghanouni
Journal: The Lancet Oncology (2022)
Abstract 3804: Interferon gamma induces NOS2 and COX2 expression in estrogen receptor negative breast cancer leading to immunosuppressive tumor microenvironment
Authors: Yuk Sing Robert Cheng, Lisa Ridnour, Veena Somasundaram, Dana Bhattacharyya, Christopher McGinity, Daniel McVicar, Stephen Anderson, Stephen Lockett, David Wink
Journal: Cancer Research (2022)

Abstract Breast cancer is the second leading cause of cancer death among U.S. women although the mortality is on a steadily decreasing trend since early 90s. We previously demonstrated a strong correlation between elevated NOS2 and COX2 expressions suggesting these genes can serve as markers of poor prognosis in estrogen receptor negative (ER-) breast cancer. In other words, NOS2 and COX2 is generally associated with the immune response. Induction of NOS2 and COX2 has also been shown to orchestrate multiple pro-oncogenic pathways that may contribute to the immunosuppressive nature of cancer cells. To better understand the interactions between cytokines and breast cancer cells and develop effective therapeutics for breast cancer, we examined the effects of selected cytokines on MDA-MB-231, a human (ER-) breast adenocarcinoma cell line. We found that in combination with cytokines, such as IFNG plus TNF, IL1B, or IL17, significantly induced NOS2 and COX2. IFNG plus TNF or IL1B most strongly induced NOS2 and COX2 where IFNG or IL17 to a lesser extent. It indicates that expressions of NOS2 and COX2 required IFNG but at a low dose in presence of other cytokines. Single-cell RNAseq analysis shows that cells treated with IFNG plus TNF or IL1B clustered with those expressed NOS2 and COX2 as revealed in tSNE plots. Expression of other factors such as IL8 and IL6 (suggested markers for prognosis of breast cancer) or PDL1 and IDO1 (suggested cancer therapeutic targets) also co-clustered with NOS2 and COX2 expressions. In addition, we found increased IL1A and IL1B expressions provide fortification to NOS2 and COX2 expressions. Taken together, our current findings indicate the interactions between breast cancer cells and cytokines. We believe further spatial transcriptomic and proteomic studies may be beneficial for clarifying the complex networks of the immunosuppressive tumor microenvironment. Citation Format: Yuk Sing Robert Cheng, Lisa Ridnour, Veena Somasundaram, Dana Bhattacharyya, Christopher McGinity, Daniel McVicar, Stephen Anderson, Stephen Lockett, David Wink. Interferon gamma induces NOS2 and COX2 expression in estrogen receptor negative breast cancer leading to immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3804.
Abstract LB021: Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression
Authors: Jason J. Northey, Yoshihiro Yui, Mary-Kate Hayward, Connor Stashko, FuiBoon Kai, Janna Mouw, Dhruv Thakar, Jonathon Lakins, Alastair Ironside, Susan Samson, Rita Mukhtar, E. Shelley Hwang, Valerie Weaver
Journal: Cancer Research (2022)

Abstract Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression. Tissue-specific factors linking stem-progenitor cell frequency to cancer risk and progression remain ill defined. Using a genetically engineered mouse model that promotes integrin mechanosignaling with syngeneic manipulations, spheroid models, and patient-derived xenografts we determined that a stiff extracellular matrix and high integrin mechanosignaling increase stem-progenitor cell frequency to enhance breast tumor risk and progression. Studies revealed that high integrin-mechanosignaling expands breast epithelial stem-progenitor cell number by potentiating progesterone receptor-dependent RANK signaling. Consistently, we observed that the stiff breast tissue from women with high mammographic density, who exhibit an increased lifetime risk for breast cancer, also have elevated RANK signaling and a high frequency of stem-progenitor epithelial cells. The findings link tissue fibrosis and integrin mechanosignaling to stem-progenitor cell frequency and causally implicate hormone signaling in this phenotype. Accordingly, inhibiting RANK signaling could temper the tumor promoting impact of fibrosis on breast cancer and reduce the elevated breast cancer risk exhibited by women with high mammographic density. Citation Format: Jason J. Northey, Yoshihiro Yui, Mary-Kate Hayward, Connor Stashko, FuiBoon Kai, Janna Mouw, Dhruv Thakar, Jonathon Lakins, Alastair Ironside, Susan Samson, Rita Mukhtar, E. Shelley Hwang, Valerie Weaver. Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB021.
Abstract 567: CRISPR/Cas9-mediated CD39 disruption can be combined with TCR editing in T cells to improve the adoptive T cell therapy of colorectal cancer
Authors: Alessia Potenza, Chiara Balestrieri, Luca Albarello, Federica Pedica, Lorena Stasi, Francesco Manfredi, Martina Spiga, Elena Tassi, Beatrice Claudia Cianciotti, Danilo Abbati, Ugo Elmore, Andrea Biondi, Luca Aldrighetti, Claudia De Lalla, Giulia Di Lullo, Paolo Dellabona, Eliana Ruggiero, Riccardo Rosati, Chiara Bonini
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the 2nd cause of cancer-related death. Despite standard therapies, more than 50% of patients experience relapse, eventually with metastatic disease. The CRC microenvironment is densely infiltrated by T-cells, which presence correlates with improved overall survival, thus sustaining the rational for immunotherapy. Here, we paired high-dimensional flow cytometry, bulk RNA sequencing and immunohistochemistry to describe the phenotype and the exhaustion status of T-cells infiltrating primary and metastatic CRC. Analysis of the healthy, peritumoral and neoplastic tissues of treatment-naïve primary CRCs and of the peritumoral and tumoral tissues of CRC patients undergoing surgery for liver metastasis, revealed extensive transcriptional and spatial remodeling across tumors. Unsupervised analysis of flow cytometry data performed by an advanced pipeline of data handling by dimensionality reduction and clustering algorithms allowed the definition of a peculiar inhibitory receptors signature on TILs enriched both in primary CRCs and liver metastases. Of note, CD39 was upregulated in both the signatures retrieved from primary and metastatic CRC, thus suggesting its relevance as molecular target for T-cells engineering. By CRISPR/Cas9 we disrupted the CD39 gene in T cells with &amp;gt;80% efficiency. We combined CD39 knock-out with the genetic disruption of alpha and beta chains of the endogenous TCR, observing &amp;gt;90% efficiency for both genes, thus generating triple-knockout T-cells. By repetitively stimulating healthy donors’ peripheral blood mononuclear cells with autologous antigen-presenting cells loaded with a pool of peptides selected to be immunogenic and expressed by CRC, we obtained a library of anti-tumor TCRs to redirected the specificity of triple knock-out lymphocytes. Our preliminary experiments showed a functional advantage for TCR-redirected, CD39 disrupted T-cells in recognizing and killing CRC target cells. Citation Format: Alessia Potenza, Chiara Balestrieri, Luca Albarello, Federica Pedica, Lorena Stasi, Francesco Manfredi, Martina Spiga, Elena Tassi, Beatrice Claudia Cianciotti, Danilo Abbati, Ugo Elmore, Andrea Biondi, Luca Aldrighetti, Claudia De Lalla, Giulia Di Lullo, Paolo Dellabona, Eliana Ruggiero, Riccardo Rosati, Chiara Bonini. CRISPR/Cas9-mediated CD39 disruption can be combined with TCR editing in T cells to improve the adoptive T cell therapy of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 567.
Abstract 6100: Chemotherapy reduces TGF-beta signaling triggered by blockade of the PD-1/PD-L1 axis
Authors: Masafumi Iida, Lucas A Horn, Haiyan Qin, Kristen Fousek, Jeffrey Schlom, Claudia Palena
Journal: Cancer Research (2022)

Abstract Combination of immune checkpoint blockade (ICB) with chemotherapy is becoming more commonly used for the treatment of various cancer types, including advanced non-small cell lung cancer, and triple negative breast cancer (TNBC) in patients who have PD-L1 positive tumors, among others. Although chemotherapy-ICB modalities have been shown to improve clinical responses over those observed with ICB alone, long-term disease control is achieved only in a small subset of patients. To provide a rational basis for combination therapy, and to potentially develop more effective approaches, in this study we investigated the impact of chemotherapy on the tumor microenvironment (TME) in the context of PD-1/PD-L1 axis blockade. ICB refractory murine models were utilized, including the TNBC 4T1 model and the Lewis Lung Carcinoma (LLC) model. Following treatments with anti-PD-L1, docetaxel, or the combination anti-PD-L1 plus docetaxel, tumors were collected 4 days after the last treatment to evaluate early changes in the TME. Analyses included the characterization of tumor immune infiltrates via flow cytometry, RNA expression profiling via RT-PCR, RNA in situ hybridization, and immunohistochemistry for detection of immune infiltrates, cancer-associated fibroblasts, and phospho-Smad2 signaling. RNA analysis of 4T1 and LLC tumors revealed a significant upregulation of several transforming growth factor-beta (TGF-beta) downstream target genes in the anti-PD-L1 monotherapy group. This increase was associated with enhanced expression of TGF-beta in the TME, as determined by RNA in situ hybridization, together with enhanced TGF-beta signaling denoted by increased expression of phospho-Smad2. Tumors treated with anti-PD-L1 monotherapy also exhibited increased numbers of alpha-smooth muscle actin positive fibroblasts in the TME. The effects observed with anti-PD-L1 as a monotherapy were not observed in tumors treated with docetaxel monotherapy or in those treated with the combination docetaxel plus anti-PD-L1 therapy, suggesting that upregulation of immunosuppressive TGF-beta signaling in the TME could be prevented by the addition of chemotherapy. Ongoing and future studies are aimed at understanding the mechanisms involved in the upregulation of TGF-beta signaling in the TME in response to anti-PD-L1 therapy in non-responsive tumors, the effect of various chemotherapies in this phenomenon, and the study of additional tumor models for optimization of chemotherapy-ICB modalities. Citation Format: Masafumi Iida, Lucas A Horn, Haiyan Qin, Kristen Fousek, Jeffrey Schlom, Claudia Palena. Chemotherapy reduces TGF-beta signaling triggered by blockade of the PD-1/PD-L1 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6100.
Abstract 2551: Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance
Authors: Yash Chhabra, Mitchell Fane, Laura Huser, Daniel Zabransky, Megan Brezka, Gloria Marino, Alexis Carey, Ashani Weeraratna
Journal: Cancer Research (2022)

Abstract Melanoma is a disease of ageing with elderly patients showing poorer prognosis than younger patients. The role of the ageing microenvironment in melanoma progression is now recognized where aged stromal cells undergo cellular and molecular changes that are tumour permissive. However, sex-based differences in melanoma incidence and outcome have also been observed even when adjusted for several prognostic factors including age, with men having poorer outcomes compared to women. While the mechanisms underlying this disparity are not well understood but attributed to sex-specific behaviors as well as to the biologically intrinsic differences. In addition, most preclinical studies have ignored the contribution of the host sex and age to therapy response, with majority of the studies typically performed in 6-8 week old male mice. Dermal fibroblasts (dFs) are established to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in dFs can alter the course of melanoma tumor growth, visceral metastasis, dormancy and variable responses to targeted therapy. We find that age-matched female dFs undergo early replicative senescence accompanied by reduced proliferation and morphology change. Despite being senescent, age-matched female dFs showed reduced SASP characteristics. This was assessed by testing dFs derived conditioned media on melanoma cells in spheroid invasion and resistance to BRAF/MEK inhibition which showed elevated expression of invasive drivers and oxidative stress from aged male dFs derived conditioned media. This was also apparent in vivo in syngeneic immunocompetent C57Bl/6 mice that showed reduced tumor growth and increased invasion specific to the aged male host. Our data provides an integrated view of how age and sex attributes of dFs within the microenvironment contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Mitchell Fane, Laura Huser, Daniel Zabransky, Megan Brezka, Gloria Marino, Alexis Carey, Ashani Weeraratna. Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2551.
Abstract 2981: Loss of the small GTPase RHOA enhances lymphomagenesis and impairs the activity of lenalidomide in mantle cell lymphoma
Authors: Juliana C. Santos, Marcelo L. Ribeiro, Gael Roue
Journal: Cancer Research (2022)

Abstract The small GTPase Ras homolog family member A (RHOA) is one of the most extensively investigated members of the Rho GTPase family, that acts as a molecular switch controlling a wide variety of signal transduction pathways. Although RHOA has long been implicated in malignant transformation in solid tumors, recent evidences have demonstrated its tumor suppressor activity in different subgroups of B-cell non-Hodgkin lymphoma (B-NHL). Here, using a panel of 11 cell lines covering the most common and/or aggressive B-NHL subtypes, we observed that the lowest mRNA and protein levels of RHOA are found in mantle cell lymphoma (MCL), the most aggressive entity with a median overall survival of 5-7 years. Depletion of RHOA expression and activity was carried out in the two RHOA+ MCL cell lines, REC-1 and Z-138, by CRISPR/Cas9-mediated gene edition followed by RHOA pulldown activation assay. In RHOA knockout (KO) subclones, cell proliferation was increased by 40%, in association with a 10-fold increase in mitotic index and a 3-fold potentiation of cell migration, as assessed respectively by CellTitter-Glo assay, histone H3-pSer10 labeling and Transwell assay, thus suggesting a tumor suppressor role of RHOA in MCL malignancy. Comparative RNA-seq analysis of RHOAWT and RHOAKO MCL subclones then highlighted a crucial role of RHOA and its downstream signaling in the control of MCL cell proliferation, cell cycle and cell migration. Interestingly, the immunomodulatory drug lenalidomide has previously shown to regulate such processes and to be clinically active in patients with relapsed/refractory MCL. In a co-culture system associating RHOAWT MCL cells with peripheral blood-derived effector cells, we observed that lenalidomide treatment facilitated the formation of immunological synapse, as revealed by simultaneous immunodetection of effector T cells, target B cells and perforin, and by quantification of lactate dehydrogenase (LDH) release. Conversely, lenalidomide exhibited minimal effect in the RHOAKO MCL co-cultures, as shown by a 30-40% decrease in the formation of immune synapse and a 4-fold decrease in LDH secretion. Taken together, these data provide the first insight into the tumor suppressive activity of RHOA in MCL and into its requirement for the immune-mediated mechanism of action of lenalidomide in this disease. Ongoing in vivo validation studies will be presented. Citation Format: Juliana C. Santos, Marcelo L. Ribeiro, Gael Roue. Loss of the small GTPase RHOA enhances lymphomagenesis and impairs the activity of lenalidomide in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2981.